REDD1 in Clear Cell Renal Cell Carcinoma: Linking Stress Adaptation, Proteostasis and Therapeutic Resistance
- 1Division of Translational Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA
- 2Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA
- 3Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of RCC and is defined by loss of von Hippel–Lindau (VHL) function and dysregulated hypoxia signaling. Hyperactivation of the mTOR pathway is also frequently observed. These factors increase anabolic and protein-synthetic demand leading to proteotoxic stress. To survive under these conditions, ccRCC cells rely on adaptive endoplasmic reticulum (ER) stress responses and autophagy to maintain proteostasis. Regulated in Development and DNA Damage Response 1 (REDD1, also known as DDIT4) is a key stress response protein that integrates hypoxic, metabolic, and ER stress signals to regulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) activity and redox homeostasis. REDD1 can either suppress tumor growth through mTOR inhibition or promote survival by facilitating oxidative stress tolerance and autophagy depending on the specific context. In ccRCC, REDD1 expression is driven by VHL loss and HIF stabilization. Yet, mTORC1 activity frequently persists due to dysregulation of upstream repressors such as TSC1/TSC2, direct activating mutations in mTOR, and enhanced growth factor signaling. This paradox underscores the complex interplay between REDD1 and the oncogenic signaling landscape of RCC. Here, we review emerging evidence positioning REDD1 as a pivotal link between hypoxia, mTOR signaling, and ER stress in ccRCC and discuss how therapeutic modulation of this pathway through ER stress inducers, proteasome inhibitors, and p97/valosin-containing protein (VCP) inhibitors may overcome adaptive resistance and improve patient outcomes.
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BibTeX
@article{sureshkumar2026redd1,
title = {{REDD1 in Clear Cell Renal Cell Carcinoma: Linking Stress Adaptation, Proteostasis and Therapeutic Resistance}},
author = {Sruthi Sureshkumar and Claudia M. Espitia and Fangchao Bi and Rui Xiong and Madison E. Gamble and Natalie L. Hakim and Kevin R. Kelly and Jennifer S. Carew and Steffan T. Nawrocki},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203358},
url = {https://www.mdpi.com/2072-6694/18/20/3358},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - REDD1 in Clear Cell Renal Cell Carcinoma: Linking Stress Adaptation, Proteostasis and Therapeutic Resistance
AU - Sruthi Sureshkumar
AU - Claudia M. Espitia
AU - Fangchao Bi
AU - Rui Xiong
AU - Madison E. Gamble
AU - Natalie L. Hakim
AU - Kevin R. Kelly
AU - Jennifer S. Carew
AU - Steffan T. Nawrocki
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203358
UR - https://www.mdpi.com/2072-6694/18/20/3358
AB - Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of RCC and is defined by loss of von Hippel–Lindau (VHL) function and dysregulated hypoxia signaling. Hyperactivation of the mTOR pathway is also frequently observed. These factors increase anabolic and protein-synthetic demand leading to proteotoxic stress. To survive under these conditions, ccRCC cells rely on adaptive endoplasmic reticulum (ER) stress responses and autophagy to maintain proteostasis. Regulated in Development and DNA Damage Response 1 (REDD1, also known as DDIT4) is a key stress response protein that integrates hypoxic, metabolic, and ER stress signals to regulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) activity and redox homeostasis. REDD1 can either suppress tumor growth through mTOR inhibition or promote survival by facilitating oxidative stress tolerance and autophagy depending on the specific context. In ccRCC, REDD1 expression is driven by VHL loss and HIF stabilization. Yet, mTORC1 activity frequently persists due to dysregulation of upstream repressors such as TSC1/TSC2, direct activating mutations in mTOR, and enhanced growth factor signaling. This paradox underscores the complex interplay between REDD1 and the oncogenic signaling landscape of RCC. Here, we review emerging evidence positioning REDD1 as a pivotal link between hypoxia, mTOR signaling, and ER stress in ccRCC and discuss how therapeutic modulation of this pathway through ER stress inducers, proteasome inhibitors, and p97/valosin-containing protein (VCP) inhibitors may overcome adaptive resistance and improve patient outcomes.
SN - 2072-6694
ER -